Alkylation of organic compounds



' Patented Sept. 19, 1944 ALKYLATION Vernon H. Wallingford, Ferguson, and August H.

Homeyer, St. Louis. Mo., assignors to Mallinckrodt Chemical Works, St. Louis,,Mo., a'corporation of Missouri No- Drawing. Application April 1 Serial No. 387,264

'8 Claims.

This invention relates to improved methods and processes for introducing alkyl, alkenyl and aralkyl groups into organic compounds.

This application is 'a continuation-in-part of our copending application, Serial Number 287,000, filed July 28, 1939.

Among the objects of this invention may be noted the provision of a general process for bringing about the alkylation, alkenylation and aralkylation of the type indicated, which is characterized by its high yields, its inexpensive and readily procurable reaction materials, and the facility with which it may be carried out. Other objects will be in part obvious and in part pointed out hereinafter. r

The invention accordingly comprises the ingredients and combinations of ingredients, the proportions thereof, steps and sequence of steps, and features of composition and synthesis, analysis, or metathesis, which will be exemplified in the products and processses hereinafter described, and the scope of the application of which will be indicated in the following claims.

In the conventional procedures compounds of the class typified by malonic esters, acetoacetic esters, other ,B-keto esters, and u-CYBHO esters are reacted in the form of their metallo derivatives, with an alkyl, alkenyl or aralkyl halide or sulfate.

The compound to be so alkylated, alkenylated or aralkylated is treated with a metal alcoholate in alcohol solution to form the metallo derivative. To this reaction mixture is then added the appropriate alkyl, alkenyl or aralkyl halide or sulfate and the reaction mixture is heated, usually at refluxing temperature until the mixture is no longer alkaline to phenolphthalein. In the case of malonic esters and alkyl, alkenyl or aralkyl halides the reaction may be shown as follows:

in which R is an organic group, Y is an organic radical, M is a metal, R is the alkyl, alkenyl or aralkyl group of the halide or sulfate. and X is a halogen or sulfate group.

We have now found that if the alkylation, alkenylation or aralkylation with alkyl, alkenyl or aralkyl halides or di-sulfates be carried out in dialkyl carbonates as reaction media, improved yields of the aligvlated or aralkylated products are obtained. In fact, in some mstances, alkylations which have heretofore been considered impossible, can be easily carried out with high yield. The dialkyl carbonates are readily available, are excellent media for reactions of the types described, and contribute great manipulative convenience to the operation.

The process of the present invention may be represented by the following equation:

where R is hydrogen or an organic group, R is an organic group, M is a metal, X-is an-organic esterifying group, R." is an alkyl, alkenyl or,

aralkyl group, Y is ahalogen or a sulfate group, and R' is the alkyl of the dialkyl carbonate. The carbon atom to which the metallo group is attached, is attached to at least two carbon atoms which are multiply bonded to atoms other than carbon.

In carrying out the presentinvention, it is necessary only to heat together the metallo compound and the alkylating alkenylating or aralkylating agent in the dialkyl carbonate.

Although it is preferred to use the diaikyl carbonate as the sole reaction medium, a portion of this may be replaced by inert solvents if desired.

The metallo group is usually the sodium compound. However, other metallo compounds such as those of the alkali metals and alkaline earth metals, may be substituted and alkylated,

EXAMPLE No. 1 v Ethylation of diethyl sea-butylmalonate Thesodio derivative of the diethyl sec.-butyl- 'malonate was prepared by treating the ester (54 4 g.) with one equivalent of alcohol-free sodium ethylate in diethyl carbonate -ml.), as de scribedin our co-pending application, Serial No. 383,164. I

To the resulting diethyl carbonate solution of the sodio derivative was then added ethyl bromide (31.5 g.) and the mixture was-refluxeduntil it ed at IOU-110 C. for six hours.

was .no longer alkaline to phenolphthalein test paper. This required about fifty hours. The reaction mixture was then cooled and stirred into about an equal volume of cold water,and then made neutral'or faintly acid to litmus with acetic acid; The organic layer was separated, the aqueous layer extracted with ether, and the combined extract and organic layer were dried with anhydrous sodium sulfate. The sodium sulfate was filtered oil, and, after stripping of! ether and diethyl carbonate, the residual ester was fractionated. A yield of 58 g. (95%) of diethyl sec.-butylethy1ma1onate was obtained. The product boiled at. 69-74 C. at about 1-3.5 mm. Its refractive index was about n 21/D 1.4331.

- Previously reported attempts by other methods to ethylate diethyl sec.-butylmalonate have given extremely small yields of the desired di- I ethyl sec.-butylethylmalonate.

I Exams No. 2 Allylation of diethyl sea-butulmalonate of the sodio derivative was then added allyl bromide (35 g.) and the resulting mixture heat- The reaction mixture was worked up as in Example 1. A yield of 55 g. (86%) of diethyl allyl-sec.-butylmalonate was obtained. This ester boiled at 109-1105 C. at about 5-6 mm., and its refractive index was aboutn 21/D 1.4430.

The ester was identified by condensing it with urea using the well-known procedure for the preparation of barbituric acid derivatives. 5,5- allyl-sec.-butyl barbituric acid, melting at 108- 109.5 C. (uncorrected), was obtained.

Exam No. 3 I Isoamulation of diethyl ethylmalonate To compare the conventional alkylation pro-- cedure with our improved method, an isoamylation of diethyl ethylmalonate in alcoholic medium was carried out concurrently with the above experiment by the well-known methods. The isoamylation of diethyl ethylmalonate in this case resulted in a yield of only 78.4 g. (61%). To indicate the independence of this alkylating procedure from the origin of the metallic derivative, the sodio derivative of diethyl ethylmalonate was prepared by the reaction of this ester with sodium metal in inert solvent, as

follows:

Sodium (7.7 g.) was granulated under toluene (30 ml.) in one liter, three-necked flask, under nitrogen, by the well-known procedure. Then benzene (100 ml.) was added, and during one aaeavee 'hour diethyl ethyimalonate (62.7 g.) was added arranged with an oil bath and a vacuum sealed stirrer.- Diethyl carbonate (200 cc.) was added and the benzene was vacuum fractionated out at 130 mm. The mixture was cooled and isoamyl bromide (50.3 g.) was added. The mixture was then stirred intermittently for ten hours at a bath temperature of -115 C. The mixture was then worked up as described in Example 1.

There 'was obtained a 75% (65 g.) yield of diethyl ethylisoamylmalonate, which boiled at -133 C. at 11 mm., and had an n 20/D of 1.4300.

' Exmu No. 4

Isoprom/lation of diethyl malonate The sodio derivative of diethyl malonate was prepared by treating the ester (42 g.) with one equivalent of alcohol-free sodium ethylate in diethyl carbonate ml.), as indicated in Example 1.

- To the resulting diethyl carbonate solution of the sodio derivative was then added isopropyl bromide (38.3 g.) and the mixture refluxed intermittently for a period of 32 hours. The reaction mixture was then worked up as described in Example 1. A yield of 43 g. (80%) of diethyl isopropylmalonate was obtained. The product boiled at 126-129 C. at about 44 mm., and its refractive index was about n 22.5/D 1.4181.

The isopropylation of diethyl malonate by the well-known Organic Syntheses procedure using alcohol as a medium for the reaction, is reported to give only 70-75% yield.

. Exmu: No. 5

'Ethulation of n-prom/l -cilano-iso-caproate The sodio derivative of ii-propyl a-cyano-isocaproate was prepared by treating the ester (39.5 g.) with one equivale'r'it of alcohol-free sodium propylate in .di-niiprdpyl carbonate (80 ml.), as indicated in Example 1. I

To the resulting di-n-propyl carbonate solution of the sodio derivative was then added ethyl bromide (25.9 g.) and the mixture stirred and heated at 95-100 C. for about five hours. The reaction mixture was then worked up as described in Example 1. A yield of 35g. (78%) of n-propyl a-cyano-a-ethyl-isocaproate, was obtained. The product boiled at 64.5-67.5 C. at about 0.4 to 0.9 mm. Its refractive index was about n 26/D 1.4298.

EXAMPLE N0. 6

Ethylation of n-butyl benzoylacetate The potassium derivative of n-butyl benzoylacetate was prepared by treating the ester '(70 g.)

with one equivalent of alcohol-free potassium 'ethylphenylmalonate, boiling at 146-150 C. at

turewas then worked up'as in Example 1. A yield 01' 63 g. (80%) of n-butyl ethyl-benzoylacetate was "obtained. The product boiled at 1l6117 C. at about 1 mm. Its refractive index was about n 26.2/D 1.5003.

Exluurta No. 7 Benzylation. of n-lmtyl cetylmalonate The potassium derivativeof di-n-butyl cetylmalonate was prepared by treating the ester (75 g.) with one equivalent of potassium butylate in di-n-butyl carbonate (175 g.), as indicated in Example 1.

To the resulting di-n-butyl carbonate solution of the potassium derivative was added benzyl chloride (24g) and the mixture was heated at 100 C. for 4 hours, at which point it was no longer alkaline to phenolphthalein. The reaction mixture was then worked up as in Example 1. A yield of 60 g. (67%) of di-n-butyl b'enzylcetylmalonate, n 27/D1.4'712, was obtained. It boiled at 238-240? C. at 1 mm.

The identity of the product was established by hydrolyzing it to the malonic acid, decarboxylating to cetylbenzylacetic acid and converting the latter to the 2,4,6-tribromoanilide which was analyzed for bromine.

A sample of the dibutyl'cetylbenzyl malonate (20 g.) was hydrolyzed by refluxing for four hours with a solution of potassium hydroxide (10 g.) in 95% alcohol (100 ml.) Water was added and alcohol was distilled off until the odor of butyl alcohol disappeared. The solution was acidified, extracted with ether and the ether extract evaporated, leaving a residue of cetylbenzyl malonic acid (17 g.) which failed to crystallize. Heating the malonic acid at 140-480 caused carbon dioxide to be evolved and cetylbenzylacetic acid was formed; after recrystallization from petroleum ether it melted at 46-47 C. A sample of of the product gave 35.1% bromine compared to the theoretical calculated for CEnI-MONBr: 01 35.0%.

EXAMPLE No. 8

Ethylatzon of diethyl phenylmalonate The sodio derivativeof diethyl phenylmalonate was prepared by treating the ester (118 g.) with one equivalent of alcohol-free sodium ethylate in diethyl carbonate (350 ml.), as indicated in Example 1.

To the resulting diethyl carbonate solution of the sodio derivative was then added ethyl bromide (65.4 g.) and the mixture heated at 95-100 C. for about five hours. The reaction mixture was worked up as in Example 1. A yield of 104 g. (19%) of diethyl ethyl phenylmalonate was ob tained. The product boiled at 135-146 C. under 4.5-6.0 mm. pressure. This grade of ester is comparable to that obtained by the conventional ethylation procedures, while the yield is substantially greater.

The above experiment was repeated, substituting diethyl sulfate (84.7 g.) for ethyl bromide and heating the reaction mixture at 105-110" C. for about five hours. It was then worked up as in Example 1. A yield of g. (84%) of diethyl 76 about 5-6 mm. .pressure, was obtained in a state oi purity superior to that usually obtained from the conventional ethylation procedure.

Theethylation of diethyl phenylmalonate with ethyl chloride can also be carried out advantageously by our procedure, as shown by the following experiment: I I

Ethyl chloride (52 g.) was dissolved in a diethyl carbonate (255 g. solution of the sodio-derivative of diethyl phenylmalonate 'g.). The resulting mixture was placed in a steel bomb and immersed in an oil bath maintained at C. The pressure in the bomb rose rapidly to 53 pounds per square inch and then diminished'slowly as the reaction proceeded. After nine hours the pressure was 37 lbs. and remained constant durreduced pressure. An 81% yield of diethyl ethylphenylmalonate (128 g.) was obtained.

To indicate the independence of this alkylating procedure from the origin of the metallo deriva-' tive, the ma'gnesio derivative of diethyl phenyle malonate was prepared and ethylated.

Magnesium turnings (6.08 g.) anhydrous ethyl alcohol (250 ml.), carbon tetrachloride (5 ml.) and diethyl phenylmalonate (59 g.) were placed in a flask fitted with reflux condenser andstirrer. The mixture was stirred, and after its initial spontaneous reaction it was heated until all of,

the magnesium had dissolved. v On cooling, a white crystalline compound crystallized. After filtering oil, the crystals were partially dried in a vacuum desiccator over calcium chloride.

About 65 g, of the solid material, still containing an appreciable amount of ethyl alcohol, was then placed in a flask containing diethyl carbonate (250 ml.). The flask was connected to a fractionating column and all residual alcohol was removed at about 150 mm. pressure. The cooled reaction mixture was then treated with ethyl iodide (43 g.), and after 48 hours heating at 95-105 C.. the reaction mixture was cooled and worked up as in Example 1. On distillation of the product a 90% yield of diethyl ethylphenylmalonate was obtained.

EXAMPLE N0. 9

Emulation of diethyl ethylmalonate The metallo derivative of diethyl ethylmalonate was prepared as described in our co-pending application, Serial No. 383,164 of March 13, 1941,

from magnesium turnings (6.0 g.), anhydrous ethyl alcohol (200 ml.) and diethyl ethylmalonate (47 g.) in diethyl carbonate (300 ml.). All ethyl alcohol present was fractionated out after the magnesium tumings had completely dissolved.

To one-halt of the resulting diethyl carbonate solution "or the magnesium derivativ of diethyl ethylmalonate was then added ethyl iodide (25 g.) and the mixture refluxed for24 hours. The reaction mixture wa 'then worked up as described in Example 1. A yield of 22 g. (83%) of diethyl diethylmalonate, was obtained. The ester boiled at 113-114 C. at about 18 mm., and its refractive index was about 11. 19.5/D 1.4240.

acetate was obtained.

Exsuru: No. 5

Allulation of diethyl malonate The sodio derivative of diethyl malonate was prepared from sodium ethylate (equivalent to 18 aassncs g. of sodium) and diethyl malonate (120 g.) in diethyl carbonate (450 m1.) as in Example 1.

The alcohol-tree reaction mixture was stirred at about 50 C. and allyl bromide (95 g.) diluted with diethyl carbonate (100 ml.) was added slowly from a dropping funnel. A solid, sodium Exmu: N0, 11

Biltvlation of diethul alllllmaldnate bromide, separated as the allyl bromide reacted The sodio, derivative 0! diethyl allylmalonate was prepared from sodium ethylate (equivalent to 8.6 g. of sodium) and diethyl allylmalonate (73.7 g.) in diethyl carbonate (250 ml.) as in Example 1.

The alcohol-free reaction mixture was stirred at about 60 C. and n-butyl bromide-(60 g.) was added slowly from a dropping funnel. A solid; sodium bromide, separated as the butyl bromide reacted with the sodio derivative of the dlethyl allylmalonate. On the following day the reaction mixture was heated to boiling to complete the reaction. The reaction mixture was workedup as in Example 1. A yield oi! 82 g. (87%) of diethyl butylallylmalonate, boiling at 129-l34 C. at 11 mm., n 20/D 1.4378, was obtained.

ExmrLn No. 12

Sea-butylatimz of di-sec.-butill malonate The potassium derivative of di-sec.-butyl malonate was prepared by treating the ester ('72 g.)

with one equivalent of potassium sec.-butylate in di-sec.-butyl carbonate (200 ml.), as indicated in Example 1 for preparation of sodio derivatives. v

To the resulting di-sec.-butyl carbonate solution of the potassium derivative was then added sea-butyl bromide (50 g.) and the mixture heated at 95-105 C. for about 70 hours. The reaction mixture was then poured into ice water, and worked up as in Example 1. A yield of 71 g. (78%) of di-sec.-butyl sec.-butyl-malonate, was

obtained. The ester boiled at 92-96 C. at about 1-2 mm. Its refractive index was about 11. 20.2/D=1.4282.

EXAMPLE N0. 13

n-Hean/latidn of ethyl acetoacetate The sodio derivative of ethyl acetoacetate was prepared by treating the ester (65 g.) with one equivalent of sodium ethylate in diethyl carbonate (250 ml), as indicated in Example 1.

To the resulting diethyl carbonate solution of the sodio derivative was then added n-hexyl bromide (90 g.), and the resulting mixture heated at 95-105 for about 50 hours. The reaction mixture was then worked up as in Example -1. A yield of 69 g. (65%) of ethyl a-n-hexylaceto- The ester boiled at 148-149 C. at about mm., and its refractive index was about mas/ 1.431s. It was further identified by its hydrolysis to methyl-n-heptyl ketone.

In view 01' the above. it will be seen that the several objects 01 the invention are achieved and other advantageous results attained.

As many changes could be made in the above processes and products without d parting from the scope of the invention, it is intended that all matter contained in the above description shall b interpreted as illustrative and not in a limitins sense.

What is claimed is:

1. The method which comprises diethyl ester of metallo sec.-butyimalonic acid,

-* wherein the metal is selected from the group consisting of alkali metals and alkaline earth metals with a substance selected from the alkyl, alkenyl and aralkyl halides and di-suliates in a reaction medium consisting essentially of a dialkyl carbonate.

2. The method which comprises reacting the npropyl ester of metallo e-cyano-iso-caproic acid, wherein the metal is selected'i'rom the group consisting of alkali metals and alkaline earth metals, with a substance selected irom the alkyl, alkenyl and aralkyl halides and di-suli'ate in a reaction medium consisting essentially of adialkyl carbonate.

3. The method which comprises reacting the ethyl ester of metallo acetoacetic acid, wherein the metal is selected from the group consisting oi alkali metals and alkaline earth metals, with a substance selected from the alkyl, alkenyl and lected from the group consisting of alkali metals and alkalineearth metals, in a vehicle consisting essentially of a dialkyl carbonate with a substance selected from the group consisting of alkyl, alkenyl and aralkyl halides and di-sulfates.

'6. The method which comprises reacting a metallo malonic ester, wherein the metal is selected from the group consisting of alkali metals and alkaline earth metals, in a vehicle consisting essentially of a dialkyl carbonate with a substance selected irom the group consisting of alkyl, alkenyl and aralkyl halides and di-sulfates.

'1. The method which comprises reacting a metallo p keto ester, wherein the metal is selected from the group consisting of alkali metals and alkaline earth metals, in a vehicle consisting essentially of a dialkyl carbonate'with a substance selected from the group consisting of alkyl, alkenyl and aralkyl halide and dl-sulfates.

8. The method which comprises reacting a metallo a cyano ester, wherein the metal is selected from the group consisting of alkali metals and alkaline earth metals, in a vehicle consisting essentially of a dialkyl carbonate with a substance selected from the group consisting of alkyl, alkenyl and aralkyl halides and di-sulfates,

- VERNON H. WALLINGFORD.

AUGUST H. HOMEYER. 

